1. Field of the Invention
The present invention relates generally to a chelating agent-conjugated α-melanocyte stimulating hormone peptide derivative, a method for the preparation thereof, and a composition for the diagnosis and treatment of melanoma comprising the same as an active ingredient.
2. Description of the Related Art
Among various skin cancers, malignant melanoma is the most dangerous type, leading to the highest mortality. A malignant tumor of melanocytes, that is, pigment-producing cells, or a nevocellular nevus is called melanoma.
In Korea, about 1˜1.5 cases of melanoma are diagnosed per 100,000 persons each year, with the morbidity increasing annually. According to a recent survey, melanoma occurs slightly more frequently in females, with a prevalence rate of 51.3%, than in males, with a prevalence rate of 48.7%. Melanoma occurs at a low rate in people under 20 years of age, but sharply increases in incidence rate among people in their forties or higher. The old, aged seventy or above, frequently suffer from melanoma. It is known that persons with lower degrees of skin pigmentation or with higher intensity or longer duration of sun exposure have a significantly greater risk for melanoma. Mutations in the cell cycle regulation genes, CDKN2A and CDK4, have been reported to increase the genetic susceptibility to melanoma tenfold.
Despite many years of intensive laboratory and clinical research, the surgical resection of primary tumors is the sole and effective cure developed to date. A number of debates have been made on sentinel lymph node biopsy for the treatment and metastatic prevention of melanoma. Additionally, an NMR spectrometer has been used for diagnosis and operation of metastasized sites. Such post-operation supplementary methods have made little progress thus far. Vaccines or cytokines have also been employed, but the use thereof in treatment has progressed only a little.
As mentioned above, melanoma can be completely cured if it is found in an early stage. If not found immediately, it rapidly spreads to other healthy parts of the body, along the lymph glands. Once they have spread, the cancer cells are hard to control. Accordingly, it is very important to find primary melanoma tumors and metastasized sites.
As it is known that current therapy is insufficient to increase the survival of patients of metastasized melanoma, intensive attention is now being paid to therapeutic agents that can effectively image melanoma tumors and take advantage of the energy emitted from radio isotopes.
Radio isotope-conjugated antibodies or antibody fragments are currently difficult to apply to the treatment of melanoma, not only because antibodies that can target melanoma-associated antigens have not yet been found, but also because antibodies under clinical and laboratory study show low tumor uptake rates and slow emission of radioisotopes from tumors. However, the finding that the melanocortin-1 receptor (MC1-R), an α-melanocyte stimulating hormone (hereinafter referred to as “α-MSH”) receptor, is expressed in human and murine melanocytes allows for various research on the image diagnosis and treatment of melanoma with radiolabeled α-MSH derivatives [Wei L, at al., J. Nucl. Med. 2007: 48: 64-72].
α-MSH is a tridecapeptide which is a class of peptide hormones produced by cells in the intermediate lobe of the pituitary gland. Of the amino acid sequence of α-MSH, the tetrapeptide His-Phe-Arg-Trp (SEQ ID NO: 8) is known to play a crucial role in recognizing the receptor, as analyzed with structure-bioactivity relationship. α-MSH is also known to increase about 1,500 times in binding affinity for the receptor when the Phe residue is modified into D-form-Phe.
In spite of the observation of the tumor uptake of radiolabeled α-MSH in animal models, they are limitedly used in practice due to the high renal retention and low tumor uptake thereof.
Leading to the present invention, intensive and thorough research on the diagnosis and treatment of primary melanoma, conducted by the present inventors, resulted in the finding that the conjugation of a chelating agent with α-MSH allows the α-MSH to be more selective for the melanocortin-1 receptor, remain in the kidney for a shorter period of time, and increase in tumor uptake.